Non-inheritable diseases
If the disease phenotype is severe enough such that it affects reproductive fitness, one could hypothesize that de novo variants-variants that emerged during meiosis of the germ cells that are unique to the offspring-are directly associated with the disease. These can be detected by performing trio-based WES on the unaffected parents and the proband, and variants that are present in the offspring only and not in the parents will be called de novo variants. The rate of de novo mutations has been shown to be relatively stable and affected primarily by paternal age [8]. WES of family quartets can also be carried out, where unaffected siblings are recruited simultaneously and their de novo mutations are compared against those of the proband. A series of studies involving autism trios and quartets recently demonstrated that rare de novo mutations were associated with the risk of autism and identified multiple de novo mutations in SCN2A, KATNAL2, and CHD8, implicating these genes in the genetic etiology underlying autism [9-11].